Epilepsy is one of the most prevalent neurological disorders. Patients with epilepsy experience recurrent seizures that can cause a variety of symptoms ranging from muscle stiffness to loss of consciousness. Partial epilepsy is the most common syndrome in adult epilepsy patients and mesial temporal lobe epilepsy (MTLE) is the most common form of partial epilepsy. Epilepsy is characterized by the abnormal synchronization of large numbers of neurons. Current therapeutic agents cannot control seizures in 25% of all epileptic patients. Although electrical stimulation of the brain has been very effective to suppress some symptoms of Parkinson's disease, the level of seizure suppression by brain stimulation has been limited. The reason for this low therapeutic outcome could be attributed to an inadequate target for stimulation, lack of understanding of the mechanisms and non-optimum stimulation parameters. During the previous grant period, we have developed a novel method to suppress seizures by activating a fiber tract target at low frequency that has been tested in several animal models and in patients with mesial temporal lobe epilepsy. We now propose to study the mechanisms underlying this powerful suppression method in order to improve the suppression and guide the clinical implementation. Specifically, we propose to 1) unravel the cellular mechanisms of the suppression and the after effects, 2) study the specific role of inhibitory neurons using optogenetics methodology and 3) determine the axonal pathways involved in the suppression. The results of this neuro-technology project should provide valuable insights into the mechanisms underlying seizure suppression as well as capitalizing on the previous grant period to develop a novel therapeutic method for the control of seizures in patients with mesial temporal lobe epilepsy.